The polymorphonuclear leukocyte (PMN) has been appreciated as an important component of a number of lung diseases, including cystic fibrosis, chronic bronchitis, and hyperoxic lung injury. Circulating PMN are known to localize to the lung under the influence of chemoattractant molecules. The central hypothesis to be explored in this proposal holds that the C5a and lL-8 receptors are major determinants mediating neutrophil migration to and activation in the lung. A secondary hypothesis is that chronic chemotactic stimulation results in tissue injury. Three specific aims are designed to test these hypotheses. Initially, we will characterize the mouse homologue of the lL-8 and IL-8 receptor system as a precursor to modelling studies. Secondly, transgenic mice constitutively expressing the lL8-homolog KC will be assessed for pathophysiologic consequences of chronic PMN activation. In the third aim, mice genetically deficient in C5a receptor or lL-8 homologue receptor will be produced and tested to address the importance of these pathways in hyperoxic lung injury, immune complex lung inflammation, as well as clearance of Pseudomonas species. The successful completion of these aims will generate a deeper understanding of the relative importance of the C5a and lL8 systems in neutrophil-mediated lung injury and defense, and be of value in directing therapeutic strategies for suppurative lung diseases.